Optic neuritis is a major cause of visual loss in healthy young adults and the first sign of multiple sclerosis in 80% of such patients. Disruption of the blood-brain barrier plays a paramount role in the pathophysiology of this autoimmune disorder of demyelination. Our recent studies in a closely related guinea pig model of reliable and reproducible immune-mediated demyelination suggest reactive oxygen metabolites, discharged by macrophages,make an important contribution to altered permeability of the blood-brain barrier and destruction of the myelin sheath. Based on these preliminary observations, we propose a hypothesis that reactive oxygen (free radical) induced disruption of the blood-brain barrier is the initial tissue alteration contributing to lipid peroxidation of myelin an demyelination of the optic nerve. In order to test this hypothesis and explore the potential for treatment with antioxidants and free radical scavengers, we will perform the following studies: (1) Assessment of endogenous production of reactive oxygen species and their relationship t blood-brain barrier permeability, by ultrastructural, histochemical localization of hydrogen peroxide in an animal model of optic nerve demyelination. (2) Suppression of altered vascular permeability induced by disruption of the blood-brain barrier and myelin peroxidation by hydrogen peroxide and reactive oxygen metabolites derived from hydrogen peroxide in experimental demyelination of the optic nerve, by exogenous administration of antioxidants and free radical scavengers. (3) Assessment of sequential stages in the disruption of the blood-brain barrier by study of magnetic resonance imaging of gadolinium leakage in the optic nerve and the effect of hydrogen peroxide detoxification in suppressing these alterations of vascular permeability during initial and chronic phases of experimental allergic encephalomyelitis.
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